A balanced control of food intake and energy expenditure is required to keep body weight in the normal range and to avoid development of obesity, which has reached epidemic proportions and is associated with costly secondary health problems. Neural circuits in the caudal brainstem are thought to play a key role in the control of food intake and energy balance, as they receive information from the alimentary canal and organize the necessary motor patterns for oropharyngeal and autonomic responses. The basic assumption of this proposal is that other key circuits in the hypothalamus, carrying longer-term metabolic and cognitive information, modulate caudal brainstem circuits concerned primarily with short-term reflex action, to achieve overall homeostatic regulation. Preliminary work by us and others has shown that (1) hypothalamic neurons expressing the "feeding peptides" melanocyte-stimulating hormone (a-MSH) and to a lesser extent agouti-related protein (AgRP), project to neurons in the caudal brainstem that receive gut signals and highly express melanocortin MC4- receptors, and (2) alpha-MSH and AgRP and their stable analogs applied directly to the caudal brainstem modulate food intake and meal size, as well as electrophysiological properties and intracellular signaling in neurons of the solitary nucleus and vagal motor nucleus. Now we propose to investigate the neurophysiological mechanisms by which alpha-MSH and AgRP modulate basic brainstem processes of ingestive control. In three specific aims we will focus on (1) the effects of the two peptides on meal structure and satiety mechanisms, (2) the connectivity and neurochemistry of the descending a-MSH and AgRP projections and the recipient neurons in the dorsal vagal complex, and (3) the neurophysiological and molecular mechanisms underlying the integration of visceral vagal and hypothalamic signals leading to changes in satiation and food intake. Our multidimensional approach using state-of-the-art behavioral, anatomical, as well as in vivo and in vitro electrophysiological and molecular techniques will provide crucial information about regulation of energy balance and will help develop therapies to prevent or combat obesity.